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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2021, Vol. 41 Issue (5): 79-86    DOI: 10.13523/j.cb.2012045
综述     
外泌体靶向递药在肿瘤治疗中的进展
吕慧中,赵晨辰,朱链(),许娜()
武汉科技大学生命科学与健康学院 生物医学研究院 武汉 430065
Progress of Using Exosome for Drug Targeted Delivery in Tumor Therapy
LV Hui-zhong,ZHAO Chen-chen,ZHU Lian(),XU Na()
Biomedical Research Institute, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065,China
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摘要：

外泌体是由细胞分泌、粒径为30~150 nm的纳米囊泡。外泌体具有优越的生物相容性、良好的载药功能以及便于修饰的膜表面,是一种具有潜力的药物递送载体。在肿瘤治疗研究中,可利用具有靶向识别功能的外泌体来降低脱靶效应,减少不良反应,达到增强治疗效果的目的。归纳了用不同修饰方法增强外泌体靶向性的研究进展,总结了近五年来利用外泌体作为特异性药物递送载体靶向治疗肿瘤的相关研究,阐述了外泌体作为新型药物递送载体的优势与不足,为设计具有靶向识别功能的外泌体提供了可行的方向与策略。
关键词： 外泌体;  药物递送载体;  修饰;  靶向;  肿瘤治疗    
Abstract:

Exosomes are nano-vesicles secreted by cells with diameter ranging from 30 to 150 nm. Attributed to superior biocompatibility, excellent loading capacity and membrane ease to be functionalized, exosomes are considered to be a promising drug delivery carrier. Among the study of tumor therapy, exosomes with targeted recognition can be used to reduce off-target effects so as to enhance the therapeutic effect. The research progresses of different modification methods to enhance the targeting ability of exosomes were concluded, the recent research using exosomes as specific drug delivery carrier to target tumor cells was summarized, and the advantages and disadvantages of exosomes as rising drug delivery carrier, which provide feasible directions and strategies for the designing of exosomes equipped with targeting specific ability were elaborated.
Key words: Exosome    Drug delivery carrier    Modification    Target    Tumor therapy
收稿日期: 2020-12-23 出版日期: 2021-06-01
ZTFLH:  Q819  
通讯作者: 朱链,许娜     E-mail: yljzl@wust.edu.cn;naxu@wust.edu.cn
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引用本文:

吕慧中,赵晨辰,朱链,许娜. 外泌体靶向递药在肿瘤治疗中的进展[J]. 中国生物工程杂志, 2021, 41(5): 79-86.

LV Hui-zhong,ZHAO Chen-chen,ZHU Lian,XU Na. Progress of Using Exosome for Drug Targeted Delivery in Tumor Therapy. China Biotechnology, 2021, 41(5): 79-86.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2012045    或    https://manu60.magtech.com.cn/biotech/CN/Y2021/V41/I5/79

图1  外泌体的结构和组成成分
图2  具有靶向识别功能外泌体药物递送载体构建示意图
肿瘤模型 来源 多肽或蛋白质 靶标 参考文献
乳腺癌 骨髓间充质干细胞 LAMP2b-DARPin 大鼠HER2/neu蛋白 [44]
HEK293T LAMP2b-DARPin 大鼠HER2/neu蛋白 [45]
间充质干细胞 LAMP2b-DARPin HER2 [46]
MCF-7 RGD 整合素 [47]
三阴性乳腺癌 人单核细胞衍生的巨噬细胞 解聚素和金属蛋白酶15(A15) 整合素 [48]
恶性黑色素瘤 HEK293T iRGD(内化型RGD) 整合素 [49]
结直肠癌 小鼠血液 ChiP(嵌合肽,包括烷基链、光敏剂PpIX
和核定位信号肽)		 细胞核 [50]
慢性粒细胞白血病 HEK293T IL-3(白介素3)-Lamp2b IL3-R(IL-3受体) [51]
肝癌 HEK293T Apo-A1(载脂蛋白A1)-CD63 SR-B1(清道夫受体B类Ⅰ型) [52]
恶性胶质瘤 Raw264.7 RGE(靶向神经毡蛋白-1的多肽) NRP-1(神经毡蛋白-1) [53]
胃癌 未成熟树突状细胞(imDCs) iRGD 整合素 [54]
宫颈癌 THP-1衍生的巨噬细胞 RGD 整合素 [35]
表1  多肽或蛋白质修饰外泌体用于靶向治疗肿瘤的相关研究
[1] Thun M J, DeLancey J O, Center M M, et al. The global burden of cancer: priorities for prevention. Carcinogenesis, 2010,31(1):100-110.
doi: 10.1093/carcin/bgp263
[2] Shi H H, Xu M, Zhu J H, et al. Programmed co-delivery of platinum nanodrugs and gemcitabine by a clustered nanocarrier for precision chemotherapy for NSCLC tumors. Journal of Materials Chemistry B, 2020,8(2):332-342.
doi: 10.1039/C9TB02055A
[3] Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nature Reviews Immunology, 2002,2(8):569-579.
doi: 10.1038/nri855
[4] Huotari J, Helenius A. Endosome maturation. The EMBO Journal, 2011,30(17):3481-3500.
doi: 10.1038/emboj.2011.286 pmid: 21878991
[5] Hessvik N P, Llorente A. Current knowledge on exosome biogenesis and release. Cellular and Molecular Life Sciences, 2018,75(2):193-208.
doi: 10.1007/s00018-017-2595-9
[6] Kowal J, Tkach M, de Théry C. Biogenesis and secretion of exosomes. Current Opinion in Cell Biology, 2014,29:116-125.
doi: 10.1016/j.ceb.2014.05.004
[7] Escola J M, Kleijmeer M J, Stoorvogel W, et al. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. Journal of Biological Chemistry, 1998,273(32):20121-20127.
doi: 10.1074/jbc.273.32.20121
[8] Eken C, Gasser O, Zenhaeusern G, et al. Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells. Journal of Immunology, 2008,180(2):817-824.
doi: 10.4049/jimmunol.180.2.817
[9] Batrakova E V, Kim M S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. Journal of Controlled Release, 2015,219:396-405.
doi: S0168-3659(15)30042-0 pmid: 26241750
[10] Chen H L, Li J J, Jiang F, et al. MicroRNA-4461 derived from bone marrow mesenchymal stem cell exosomes inhibits tumorigenesis by downregulating COPB2 expression in colorectal cancer. Bioscience, Biotechnology, and Biochemistry, 2020,84(2):338-346.
doi: 10.1080/09168451.2019.1677452
[11] Katakowski M, Buller B, Zheng X G, et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Letters, 2013,335(1):201-204.
doi: 10.1016/j.canlet.2013.02.019 pmid: 23419525
[12] Ono M, Kosaka N, Tominaga N, et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Science Signaling, 2014, 7(332): ra63.
doi: 10.1126/scisignal.2005231
[13] Xie C, Du L Y, Guo F Y, et al. Exosomes derived from microRNA-101-3p-overexpressing human bone marrow mesenchymal stem cells suppress oral cancer cell proliferation, invasion, and migration. Molecular and Cellular Biochemistry, 2019,458(1-2):11-26.
doi: 10.1007/s11010-019-03526-7
[14] Sanderson R D, Bandari S K, Vlodavsky I. Proteases and glycosidases on the surface of exosomes: Newly discovered mechanisms for extracellular remodeling. Matrix Biology, 2019, 75-76:160-169.
[15] Ludwig N, Gillespie D G, Reichert T E, et al. Purine metabolites in tumor-derived exosomes may facilitate immune escape of head and neck squamous cell carcinoma. Cancers, 2020,12(6):1602.
doi: 10.3390/cancers12061602
[16] Haderk F, Schulz R, Iskar M, et al. Tumor-derived exosomes modulate PD-L1 expression in monocytes. Science Immunology, 2017, 2(13): eaah5509.
[17] Johnsen K B, Gudbergsson J M, Skov M N, et al. A comprehensive overview of exosomes as drug delivery vehicles:Endogenous nanocarriers for targeted cancer therapy. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2014,1846(1):75-87.
doi: 10.1016/j.bbcan.2014.04.005
[18] Gallatin W M, Weissman I L, Butcher E C. A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature, 1983,304(5921):30-34.
pmid: 6866086
[19] Liesveld J L, Sharma N, Aljitawi O S. Stem cell homing: From physiology to therapeutics. Stem Cells (Dayton, Ohio), 2020,38(10):1241-1253.
[20] 李艾, 张添源, 高建青. 间充质干细胞的肿瘤归巢特性及其肿瘤靶向治疗应用研究进展. 浙江大学学报(医学版), 2020,49(1):20-34.
Li A, Zhang T Y, Gao J Q. Progress on utilizing mesenchymal stem cells as cellular delivery system for targeting delivery of as drug/gene for anti-tumor therapy. Journal of Zhejiang University (Medical Sciences), 2020,49(1):20-34.
[21] Harrell C R, Jovicic N, Djonov V, et al. Therapeutic use of mesenchymal stem cell-derived exosomes: from basic science to clinics. Pharmaceutics, 2020,12(5):474.
doi: 10.3390/pharmaceutics12050474
[22] Myint P K, Park E J, Gaowa A, et al. Targeted remodeling of breast cancer and immune cell homing niches by exosomal integrins. Diagnostic Pathology, 2020,15(1):38.
doi: 10.1186/s13000-020-00959-3
[23] Zhou Y, Zhou W X, Chen X L, et al. Bone marrow mesenchymal stem cells-derived exosomes for penetrating and targeted chemotherapy of pancreatic cancer. Acta Pharmaceutica Sinica B, 2020,10(8):1563-1575.
doi: 10.1016/j.apsb.2019.11.013 pmid: 32963950
[24] Wei H X, Chen J Y, Wang S L, et al. A nanodrug consisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma treatment in vitro. International Journal of Nanomedicine, 2019,14:8603-8610.
doi: 10.2147/IJN
[25] Qiao L, Hu S Q, Huang K, et al. Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs. Theranostics, 2020,10(8):3474-3487.
doi: 10.7150/thno.39434 pmid: 32206102
[26] Yong T Y, Zhang X Q, Bie N N, et al. Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy. Nature Communications, 2019,10:3838.
doi: 10.1038/s41467-019-11718-4
[27] Zhao L W, Gu C Y, Gan Y, et al. Exosome-mediated siRNA delivery to suppress postoperative breast cancer metastasis. Journal of Controlled Release, 2020,318:1-15.
doi: 10.1016/j.jconrel.2019.12.005
[28] Smyth T, Kullberg M, Malik N, et al. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. Journal of Controlled Release, 2015,199:145-155.
doi: 10.1016/j.jconrel.2014.12.013
[29] Zhu W, Huang L, Li Y H, et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Letters, 2012,315(1):28-37.
doi: 10.1016/j.canlet.2011.10.002
[30] Chapel A, Bertho J M, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. The Journal of Gene Medicine, 2003,5(12):1028-1038.
doi: 10.1002/(ISSN)1521-2254
[31] Munagala R, Aqil F, Jeyabalan J, et al. Bovine milk-derived exosomes for drug delivery. Cancer Letters, 2016,371(1):48-61.
doi: 10.1016/j.canlet.2015.10.020 pmid: 26604130
[32] Li Z F, Wang H Z, Yin H R, et al. Arrowtail RNA for ligand display on ginger exosome-like nanovesicles to systemic deliver siRNA for cancer suppression. Scientific Reports, 2018,8:14644.
doi: 10.1038/s41598-018-32953-7
[33] Zheng Z, Li Z F, Xu C C, et al. Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping. Journal of Controlled Release, 2019, 311-312:43-49.
doi: S0168-3659(19)30505-X pmid: 31446085
[34] Yu M Y, Gai C C, Li Z, et al. Targeted exosome-encapsulated erastin induced ferroptosis in triple negative breast cancer cells. Cancer Science, 2019,110(10):3173-3182.
doi: 10.1111/cas.v110.10
[35] Wang J, Dong Y, Li Y W, et al. Designer exosomes for active targeted chemo-photothermal synergistic tumor therapy. Advanced Functional Materials, 2018,28(18):1707360.
doi: 10.1002/adfm.v28.18
[36] Large D E, Soucy J R, Hebert J, et al. Advances in receptor-mediated, tumor-targeted drug delivery. Advanced Therapeutics, 2019,2(1):1800091.
doi: 10.1002/adtp.v2.1
Large D E, Soucy J R, Hebert J, et al. Advances in receptor-mediated, tumor-targeted drug delivery. Advanced Therapeutics, 2019,2(1):1800091.
[37] Nie W D, Wu G H, Zhang J F, et al. Responsive exosome nano-bioconjugates for synergistic cancer therapy. Angewandte Chemie (International Ed in English), 2020,59(5):2018-2022.
doi: 10.1002/anie.v59.5
[38] Cheng Q Q, Shi X J, Han M L, et al. Reprogramming exosomes as nanoscale controllers of cellular immunity. Journal of the American Chemical Society, 2018,140(48):16413-16417.
doi: 10.1021/jacs.8b10047
[39] Shi X J, Cheng Q Q, Hou T L, et al. Genetically engineered cell-derived nanoparticles for targeted breast cancer immunotherapy. Molecular Therapy, 2020,28(2):536-547.
doi: 10.1016/j.ymthe.2019.11.020
[40] Si Y N, Kim S, Zhang E, et al. Targeted exosomes for drug delivery: biomanufacturing, surface tagging, and validation. Biotechnology Journal, 2020,15(1):e1900163.
[41] Li Y, Gao Y, Gong C N, et al. A33 antibody-functionalized exosomes for targeted delivery of doxorubicin against colorectal cancer. Nanomedicine: Nanotechnology, Biology and Medicine, 2018,14(7):1973-1985.
doi: 10.1016/j.nano.2018.05.020
[42] Samaranayake H, Wirth T, Schenkwein D, et al. Challenges in monoclonal antibody-based therapies. Annals of Medicine, 2009,41(5):322-331.
doi: 10.1080/07853890802698842 pmid: 19234897
[43] Hung M E, Leonard J N. Stabilization of exosome-targeting peptides via engineered glycosylation. Journal of Biological Chemistry, 2015,290(13):8166-8172.
doi: 10.1074/jbc.M114.621383
[44] Gomari H, Moghadam M F, Soleimani M, et al. Targeted delivery of doxorubicin to HER2 positive tumor models. International Journal of Nanomedicine, 2019,14:5679-5690.
doi: 10.2147/IJN.S210731 pmid: 31413568
[45] Limoni S K, Moghadam M F, Moazzeni S M, et al. Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells. Applied Biochemistry and Biotechnology, 2019,187(1):352-364.
doi: 10.1007/s12010-018-2813-4
[46] Gomari H, Moghadam M F, Soleimani M. Targeted cancer therapy using engineered exosome as a natural drug delivery vehicle. OncoTargets and Therapy, 2018,11:5753-5762.
doi: 10.2147/OTT.S173110 pmid: 30254468
[47] Cao Y, Wu T T, Zhang K, et al. Engineered exosome-mediated near-infrared-II region V2C quantum dot delivery for nucleus-target low-temperature photothermal therapy. ACS Nano, 2019,13(2):1499-1510.
doi: 10.1021/acsnano.8b07224 pmid: 30677286
[48] Gong C N, Tian J, Wang Z, et al. Functional exosome-mediated co-delivery of doxorubicin and hydrophobically modified microRNA 159 for triple-negative breast cancer therapy. Journal of Nanobiotechnology, 2019,17(1):93.
doi: 10.1186/s12951-019-0526-7
[49] 赵莉娟, 郑江红, 柳向东, 等. iRGD-外泌体-阿霉素抑制恶性黑色素瘤体外增殖的研究. 组织工程与重建外科杂志, 2017,13(1):25-28.
Zhao L J, Zheng J H, Liu X D, et al. The inhibition of iRGD-exosomes-doxorubicin on the proliferation of malignant melanoma in vitro. Journal of Tissue Engineering and Reconstructive Surgery, 2017,13(1):25-28.
[50] Cheng H, Fan J H, Zhao L P, et al. Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy. Biomaterials, 2019,211:14-24.
doi: S0142-9612(19)30268-6 pmid: 31078049
[51] Bellavia D, Raimondo S, Calabrese G, et al. Interleukin 3- receptor targeted exosomes inhibit in vitro and in vivo Chronic Myelogenous Leukemia cell growth. Theranostics, 2017,7(5):1333-1345.
doi: 10.7150/thno.17092 pmid: 28435469
[52] Liang G F, Kan S, Zhu Y L, et al. Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells. International Journal of Nanomedicine, 2018,13:585-599.
doi: 10.2147/IJN
[53] Jia G, Han Y, An Y L, et al. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials, 2018,178:302-316.
doi: 10.1016/j.biomaterials.2018.06.029
[54] Xin L, Yuan Y W, Liu C, et al. Preparation of internalizing RGD-modified recombinant methioninase exosome active targeting vector and antitumor effect evaluation. Digestive Diseases and Sciences, 2021,66(4):1045-1053.
doi: 10.1007/s10620-020-06262-x
[55] Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proceedings of the National Academy of Sciences of the United States of America, 1989,86(24):10024-10028.
[56] Porter D L, Levine B L, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. The New England Journal of Medicine, 2011,365(8):725-733.
doi: 10.1056/NEJMoa1103849 pmid: 21830940
[57] Jackson H J, Rafiq S, Brentjens R J. Driving CAR T-cells forward. Nature Reviews Clinical Oncology, 2016,13(6):370-383.
doi: 10.1038/nrclinonc.2016.36
[58] Mahadeo K M, Khazal S J, Abdel-Azim H, et al. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nature Reviews Clinical Oncology, 2019,16(1):45-63.
doi: 10.1038/s41571-018-0075-2
[59] Newick K, O’Brien S, Moon E, et al. CAR T cell therapy for solid tumors. Annual Review of Medicine, 2017,68(1):139-152.
doi: 10.1146/annurev-med-062315-120245
[60] Brudno J N, Kochenderfer J N. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 2016,127(26):3321-3330.
doi: 10.1182/blood-2016-04-703751
[61] Maude S L, Barrett D, Teachey D T, et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies. The Cancer Journal, 2014,20(2):119-122.
doi: 10.1097/PPO.0000000000000035
[62] Tang X J, Sun X Y, Huang K M, et al. Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy. Oncotarget, 2015,6(42):44179-44190.
doi: 10.18632/oncotarget.v6i42
[63] Fu W Y, Lei C H, Liu S W, et al. CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity. Nature Communications, 2019,10:4355.
doi: 10.1038/s41467-019-12321-3
[64] Rafiq S, Hackett C S, Brentjens R J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nature Reviews Clinical Oncology, 2020,17(3):147-167.
doi: 10.1038/s41571-019-0297-y
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